Dissertation Archive, WMU Graduate College

Dissertation Defense

Candidate: Berta Rebimbas-Cohen

Degree of: Doctor of Philosophy

Department: Biological Sciences

Title: Changes in Glial Cell Line Derived Neurotrophic Factor and Nerve Growth Factor Expression With Development, Age, Exercise and Hypertension

Date: Friday, July 9, 2004 11:00a.m.-1:00p.m.
2902 Wood Hall

Committee: Dr. John Spitsbergen, Chair
Dr. William Jackson
Dr. John Jellies
Dr. Susan Stapleton

Abstract: Neurotrophic factors are important for neuronal growth, survival, and maintenance of cell phenotype. Glial cell line-derived neurotrophic factor (GDNF) affects sensory, autonomic and somatic motor neurons and nerve growth factor (NGF) affects sensory and sympathetic neurons. NGF and GDNF are produced by cardiac muscle and have potent effects on sensory and autonomic neuronal innervation of blood vessels. Recent studies have shown that different populations of sympathetic neurons innervate mesenteric arteries and veins and that neural innervation plays a key role in blood vessel function. Since neural innervation of blood vessels may be regulated by these growth factors, we wanted to determine whether levels of expression of NGF and GDNF differ in arteries and veins that receive neural innervation and whether NGF and GDNF levels change with aging and exercise thus altering innervation patterns. In our studies we chose to explore the following three questions: 1. Are GDNF and NGF present in the mesenteric vessel bed and if so, does protein content change with age, maturation and exercise? 2. Does GDNF expression change with the development of hypertension? 3. Do GDNF or NGF have differential expression in cardiac tissue with age, development and exercise?

Change in GDNF and NGF expression and innervation were examined in the mesenteric arteries, veins and hearts from Fisher 344 rats, which were exercised for 14 weeks and then two rat models of hypertension, Dahl salt sensitive (SS/JR) rats and Fischer 344 rats treated with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Protein levels will be examined using enzyme linked immunosorbant assay (ELISA). Innervation density was studied using immunohistochemical methods. To determine if increased pressure can act as a stimulus for increased GDNF expression in arteries, isolated cannulated vessel experiments were performed.

We found GDNF levels were significantly higher in mesenteric veins versus mesenteric arteries. NGF levels were significantly higher in arteries and veins of 8 wk old animals versus arteries and veins of 22 wk animals. The localization of NGF and GDNF in blood vessels in sedentary animals was within fibers staining positive for tyrosine hydroxylase (TH) indicating colocalization with sympathetic neuron. However, in young or exercised older animals these growth factors were colocalized with calcitonin gene related peptide (CGRP), a marker of sensory innervation, which indicates a dilating factor. In addition, the amount of sympathetic innervation increased as the animals aged and became sedentary and this increase was paralleled by a comparable decrease in blood pressure.

Our study also determined in NGF and GDNF expression in cardiac muscle was regulated by exercise in the form of voluntary running in running wheels. Fourteen weeks of exercise had little effect on the NGF protein content in atria or ventricle but led to an increase in GDNF content in the left and right aria and ventricles. Activity dependent regulation of trophic factor in the heart may play a role in altered nerve structure and function observed following exercise training.

Finally, we determined if GDNF expression changed with the development of hypertension by performing a set of in vivo an in vitro experiments. In the SS/JR and LNAME models of hypertension, GDNF protein content was found to be elevated in the vessels of hypertension animals. In In vitro studies, 4 hours of elevated pressure increased the GDNF protein content increased above controls. Taken together all these data suggests that both NGF and GDNF may be regulated in an exercise dependent manner, change with aging, are increased by exercise training, and may be a factor in the development or maintenance of hypertension.

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